title: Hydantoin based inhibitors of MMP13--discovery of AZD6605.
abstract: Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.
authors.affiliation: Oncology Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. chris.desavi2@astrazeneca.com
authors.forename: Chris
authors.initials: C
authors.lastname: De Savi
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Andrew
authors.initials: A
authors.lastname: Pape
authors.forename: Scott
authors.initials: S
authors.lastname: Lamont
authors.forename: Elma
authors.initials: E
authors.lastname: Hadley
authors.forename: Mark
authors.initials: M
authors.lastname: Mills
authors.forename: Ken M
authors.initials: KM
authors.lastname: Page
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bowyer
authors.forename: Rose A
authors.initials: RA
authors.lastname: Maciewicz
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C585976:AZD6605; D006827:Hydantoins; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053509:Matrix Metalloproteinase 13
keywords: Cyp P450; Hydantoin; Lead optimisation; MMP13; Zinc binder